Gamma d-Crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

ABSTRACT

A γd-Crystalline form of ivabradine hydrochloride of formula (I):  
                 
characterised by its powder X-ray diffraction data. Medicinal products containing the same which are useful as bradycardics.

The present invention relates to the new γd-crystalline form of ivabradine hydrochloride of formula (I), to a process for its preparation and to pharmaceutical compositions containing it.

Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.

In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.

The patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining ivabradine in a form that exhibits those characteristics in a reproducible manner.

The Applicant has now found that a particular salt of ivabradine, the hydrochloride, can be obtained in a crystalline form that is well defined and that exhibits valuable characteristics of stability and processability.

More specifically, the present invention relates to the γd-crystalline form of ivabradine hydrochloride, which is characterised by the following powder X-ray diffraction diagram measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Angle Interplanar Ray 2 theta Height Area FWHM distance no. (degrees) (counts) (counts × degrees) (degrees) (Å)  1 4.3 1077 124 0.1171 20.633  2 6.9 132 70 0.5353 12.787  3 8.4 269 35 0.1338 10.482  4 10.6 322 26 0.0836 8.310  5 11.9 733 97 0.1338 7.414  6 12.5 1406 278 0.2007 7.069  7 13.4 2975 442 0.1506 6.619  8 14.4 825 122 0.1506 6.134  9 15.8 1036 205 0.2007 5.598 10 16.3 540 107 0.2007 5.450 11 16.9 1007 183 0.184 5.233 12 17.8 499 58 0.1171 4.978 13 18.9 1062 140 0.1338 4.686 14 19.8 570 85 0.1506 4.485 15 20.2 549 63 0.1171 4.399 16 20.9 2565 635 0.2509 4.241 17 21.6 531 105 0.2007 4.104 18 22.3 213 35 0.1673 3.981 19 23.4 278 27 0.1004 3.807 20 24.1 1404 185 0.1338 3.694 21 24.4 1526 176 0.1171 3.650 22 24.8 676 100 0.1506 3.591 23 25.4 702 139 0.2007 3.504 24 26.2 1737 401 0.2342 3.403 25 26.8 258 51 0.2007 3.331 26 27.2 182 24 0.1338 3.282 27 27.9 838 249 0.3011 3.193 28 29.1 152 20 0.1338 3.071

The invention relates also to a process for the preparation of the γd-crystalline form of ivabradine hydrochloride, which process is characterised in that a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallisation is complete, and the crystals obtained are collected by filtration and dehydrated.

-   -   In the crystallisation process according to the invention it is         possible to use ivabradine hydrochloride obtained by any         process, for example ivabradine hydrochloride obtained by the         preparation process described in patent specification EP 0 534         859.     -   The solution may advantageously be seeded during the cooling         step.

The invention relates also to pharmaceutical compositions comprising as active ingredient the γd-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert, nontoxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions.

The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. That dosage varies from 1 to 500 mg per day in one or more administrations.

The following Examples illustrate the invention.

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

-   PANalytical X'Pert Pro diffractometer, X'Celerator detector,     temperature-regulated chamber, -   voltage 45 kV, intensity 40 mA, -   mounting θ-θ, -   nickel (Kβ) filter, -   incident-beam and diffracted-beam Soller slit: 0.04 rad, -   fixed angle of divergence slits: ⅛°, -   mask: 10 mm, -   antiscatter slit: ¼°, -   measurement mode: continuous from 3° to 30°, in increments of     0.017°, -   measurement time per step: 19.7 s, -   total time: 4 min 32 s, -   measurement speed: 0.108°/s, -   measurement temperature: ambient.

EXAMPLE 1 γd-Crystalline Form of Ivabradine Hydrochloride

40 ml of 2-ethoxyethanol are preheated to 80° C., and then 8.4 g of ivabradine hydrochloride obtained according to the process described in the patent specification EP 0 534 859 are added in portions, with stirring, and the mixture is heated at 80° C. until dissolution is complete. After returning to ambient temperature, the solution is stored for 8 days, and then the crystals formed are collected by filtration and rinsed with cyclohexane.

The product thereby obtained is dehydrated by progressively heating at a rate of 5° C./min up to a temperature of 80° C.

X-ray powder diffraction diagram:

The X-ray powder diffraction profile (diffraction angles) of the γd-form of ivabradine hydrochloride is given by the significant rays collated in the following table: Angle Interplanar Ray 2 theta Height Area FWHM distance no. (degrees) (counts) (counts × degrees) (degrees) (Å)  1 4.3 1077 124 0.1171 20.633  2 6.9 132 70 0.5353 12.787  3 8.4 269 35 0.1338 10.482  4 10.6 322 26 0.0836 8.310  5 11.9 733 97 0.1338 7.414  6 12.5 1406 278 0.2007 7.069  7 13.4 2975 442 0.1506 6.619  8 14.4 825 122 0.1506 6.134  9 15.8 1036 205 0.2007 5.598 10 16.3 540 107 0.2007 5.450 11 16.9 1007 183 0.184 5.233 12 17.8 499 58 0.1171 4.978 13 18.9 1062 140 0.1338 4.686 14 19.8 570 85 0.1506 4.485 15 20.2 549 63 0.1171 4.399 16 20.9 2565 635 0.2509 4.241 17 21.6 531 105 0.2007 4.104 18 22.3 213 35 0.1673 3.981 19 23.4 278 27 0.1004 3.807 20 24.1 1404 185 0.1338 3.694 21 24.4 1526 176 0.1171 3.650 22 24.8 676 100 0.1506 3.591 23 25.4 702 139 0.2007 3.504 24 26.2 1737 401 0.2342 3.403 25 26.8 258 51 0.2007 3.331 26 27.2 182 24 0.1338 3.282 27 27.9 838 249 0.3011 3.193 28 29.1 152 20 0.1338 3.071

EXAMPLE 2 Pharmaceutical Composition

Formula for the preparation of 1000 tablets each containing 5 mg of ivabradine base: Compound of Example 1 5.39 g Maize starch 20 g Anhydrous colloidal silica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g 

1. A γd-Crystalline form of ivabradine hydrochloride of formula (I):

exhibiting essentially the following powder X-ray diffraction data measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts, ray area (expressed in counts x degrees), ray width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Angle Interplanar Ray 2 theta Height Area FWHM distance no. (degrees) (counts) (counts × degrees) (degrees) (Å)  1 4.3 1077 124 0.1171 20.633  2 6.9 132 70 0.5353 12.787  3 8.4 269 35 0.1338 10.482  4 10.6 322 26 0.0836 8.310  5 11.9 733 97 0.1338 7.414  6 12.5 1406 278 0.2007 7.069  7 13.4 2975 442 0.1506 6.619  8 14.4 825 122 0.1506 6.134  9 15.8 1036 205 0.2007 5.598 10 16.3 540 107 0.2007 5.450 11 16.9 1007 183 0.184 5.233 12 17.8 499 58 0.1171 4.978 13 18.9 1062 140 0.1338 4.686 14 19.8 570 85 0.1506 4.485 15 20.2 549 63 0.1171 4.399 16 20.9 2565 635 0.2509 4.241 17 21.6 531 105 0.2007 4.104 18 22.3 213 35 0.1673 3.981 19 23.4 278 27 0.1004 3.807 20 24.1 1404 185 0.1338 3.694 21 24.4 1526 176 0.1171 3.650 22 24.8 676 100 0.1506 3.591 23 25.4 702 139 0.2007 3.504 24 26.2 1737 401 0.2342 3.403 25 26.8 258 51 0.2007 3.331 26 27.2 182 24 0.1338 3.282 27 27.9 838 249 0.3011 3.193 28 29.1 152 20 0.1338 3.071


2. A process for the preparation of the γd-crystalline form of ivabradine hydrochloride of claim 1, wherein a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the crystals thus obtained are collected by filtration and dehydrated.
 3. The process of claim 2, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.
 4. A pharmaceutical composition comprising as active ingredient the γd-crystalline form of ivabradine hydrochloride of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
 5. A method for treating or preventing a condition requiring a bradycardic, such method comprising administering to a living animal body, including a human, a therapeutically effective amount of a γd-crystalline form of ivabradine hydrochloride of claim
 1. 6. A method for treating or preventing clinical situations of myocardial ischaemia and/or a condition involving rhythm disturbances such method comprising administering to a living animal body, including a human, a therapeutically effective amount of a γd-crystalline form of ivabradine hydrochloride of claim
 1. 7. The method of claim 6, wherein the clinical situation of myocardial ischaemia is selected from angina pectioris and myocardial infarct and associated rhythm disturbances.
 8. The method of claim 6, wherein the condition involving rhythm disturbances is selected from supra ventricular rhythm disturbances and heart failure. 